Sunday, February 5, 2012

IRA B cells: going beyond IgM defense line

B cells produce antibodies that clear pathogen from body tissues and protect against re-infection. In general, there are two types of B cells. One type, called innate-like, produce Ab when stimulated by bacterial ligands alone (for example, LPS). 2nd type of B cell require additional T cell-derived signals to produce Ab. While T-dependent Ab production is well-described, little is known about innate-like B cells, their function or contribution to the protection against pathogens.

If you are interested to know more about innate-like B cells, I will recommend reading new paper published in Science. In this study (1) by Rauch, Chudnovskiy, Robbins et al, the authors made surprising observation that in response peritoneal injection of TLR4 ligand, LPS, the predominant cell population in the spleen producing granulocyte-macrophage colony-stimulating factor (GM-CSF) were B cells (Fig 1). The authors dubbed these cells innate response activator (IRA) B cells. The phenotype of IRA B cells producing GM-CSF showed that they were derived from innate-like B cells, also known as B1a cells (Fig 2B). The authors showed that direct signaling through TLR in B1a cells was necessary to develop into IRA B cells (Fig. 3E). By creating mixed chimera where only B cell were deficient in producing GM-CSF, the authors showed that absence of IRA B cells compromised bacterial clearance from the blood (Fig. 4I) in mouse model of peritonitis (sepsis model) and reduced survival rate compared to control [0 vs. 40% survival 72h post peritonitis onset] (Fig 4B).

It has been known for some time that B1a cells from peritoneal cavity migrate into spleen upon activation. Until now, the thinking was that they differentiate into plasma cells producing poly-reactive innate IgM. However, this is a first report to show that besides IgM production, IRA B cells carry another important message, namely GM-CSF, that may influence other cells (macrophages, DCs, neutrophils) to participate in response against pathogens. However, at this stage, it is not clear how exactly IRA B cell-derived GM-CSF has such a protective effect.

P.S.Analogous observation regarding B cells was recently described in Nature. There (2), the authors showed that iNOS/TNF-alpha producing B cells in the gut play a protective role during immune response to C. rodentium.